Ortho C-H acylation of aryl iodides by palladium/norbornene catalysis

Article abstract of DOI:10.1002/anie.201506397

Reported herein is a palladium/norbornene-catalyzed ortho-arene acylation of aryl iodides by a Catellani-type C-H functionalization. This transformation is enabled by isopropyl carbonate anhydrides, which serve as both an acyl cation equivalent and a hydride source. Double (re)agent: A palladium/norbornene-catalyzed ortho-acylation of aryl iodides was developed, and is enabled by isopropyl carbonate anhydrides, which function as both an acyl cation equivalent and a hydride source. This reaction exhibits excellent functional-group compatibility and broad substrate scope. Heterocycle moieties can be tolerated on both the aryl and acyl partners. FG=functional group.

Full text of DOI:10.1002/anie.201506397

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Communications
International Edition: DOI: 10.1002/anie.201506397
German Edition: DOI: 10.1002/ange.201506397
À
C H Activation
À
Ortho C H Acylation of Aryl Iodides by Palladium/Norbornene
Catalysis
Zhe Dong, Jianchun Wang, Zhi Ren, and Guangbin Dong*
Dedicated to Professor Stephen L. Buchwald on the occasion of his 60th birthday
Abstract: Reported herein is a palladium/norbornene-cata-
lyzed ortho-arene acylation of aryl iodides by a Catellani-type
À
C H functionalization. This transformation is enabled by
isopropyl carbonate anhydrides, which serve as both an acyl
cation equivalent and a hydride source.
A
romatic ketones are widely found in pharmaceuticals,[1]
agrochemicals,[2] organic electrons,[3] and polymers.[4] They
have also been frequently utilized as dyes,[5] photolabels,[6]
and photosensitizers.[4a,7] Further transformation of the car-
bonyl group provides a generic entry to compounds contain-
ing a benzylic functionality. Conventionally, aryl ketones are
synthesized by the Friedel–Crafts acylation[8] of arenes using
strong Lewis acids. Generally, the site selectivity is dominated
by the electronic preference of the substrates. Addition of aryl
nucleophiles to carbonyl compounds[9] and carbonylative
cross-couplings[10] represent two effective methods to prepare
aryl ketones from prefunctionalized arenes (e.g. aryl halides)
to give ipso-substituted products. Transition-metal-catalyzed
Scheme 1. Palladium/norbornene catalysis. Bz=benzoyl, FG=func-
tional group.
À
arene C H activation/acylation offers a distinct approach, but
use of a directing group[11] is usually critical. Given the wide
availability of aryl halides, here, a complementary strategy for
aryl ketone synthesis was sought through introducing an acyl
group to the ortho-position of iodoarenes by using palladium/
norbornene (NBE) catalysis.
The Pd/NBE chemistry, originally discovered by Catellani
et al.,[12] allows activation of both the ipso and ortho-positions
of arenes with aryl halides as substrates (Scheme 1a).[12c–e, 13]
This reaction is initiated by palladium(0) oxidative addition to
[14]
À
À
the Ar X bond and subsequent NBE-mediated vicinal C
H metalation to generate a unique electron-rich aryl/NBE
palladacycle (ANP),[15] which can react with an electrophile to
introduce a functional group (FG) at the ortho-position
(Figure 1).[16] Subsequent de-insertion of NBE through b-
carbon elimination gives back an aryl palladium (Ar-Pd-X)
species (G), which can then be trapped by a nucleophile (or
an olefin) to furnish the ipso functionalization and regenerate
the palladium(0) catalyst.[12a] Seminal work by the groups of
Catellani and Lautens[12a,b, 17] showed that a variety of FGs can
Figure 1. Proposed catalytic cycle.
be installed at the ipso-carbon atom by choosing different
nucleophiles. However, functionalization at the ortho-posi-
tion was previously restricted to alkylation and arylation.[12a,18]
Recently, ortho amination was realized by using benzoyloxy-
amines as the reagent.[19] Nevertheless, introduction of other
FGs at the ortho-position remains challenging, mainly
because of the difficulty of selective oxidation of the ANP
intermediate versus the initial palladium(0) catalyst.
[*] Z. Dong,[+] J. Wang,[+] Z. Ren, Prof. Dr. G. Dong
Department of Chemistry, University of Texas at Austin
100 East 24th street, Austin, TX 78712 (USA)
E-mail: gbdong@cm.utexas.edu
Homepage: http://gbdong.cm.utexas.edu/
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201506397.
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We hypothesized that a properly masked acyl cation could
selectively react with the electron-rich ANP intermediate to
an enhanced yield, and importantly ease of isolation of the
desired product from NBE-containing byproducts.[23] The use
of NMe4Cl as an additive is not critical (entry 7), but was
found to be beneficial to reduce side reactions involving
reduction of the ANP intermediate.[24] Among all the
phosphine ligands tested, the more-electron-deficient tri(2-
furyl)phosphine gave the optimal results (entry 9).[17b] Use of
potassium carbonate as a base dramatically decreased the
yield (entry 10). Addition of acetonitrile as a minor cosolvent
was expected to assist de-chelation of the ketone carbonyl
from the palladium intermediate; in pure THF the yield was
lower[25] (entry 11). Finally, the reaction can still proceed at
608C albeit requiring a longer reaction time (entry 12).
The scope of the aryl iodides was examined first (Table 2).
Gratifyingly, aryl iodides with various electron properties
reacted well to afford the meta-substituted aryl ketones.[26]
When electron-deficient aryl iodides were used, additional
benzoyl anhydride and a lower reaction temperature were
required to prevent homodimerization.[12b] Moreover, reac-
tions with these substrates gave higher yields in the absence of
À
form the ortho aryl acyl bond through either a palladium(IV)
intermediate or direct electrophilic substitution (Figure 1). In
the presence of a suitable hydride source, hydrogen would be
introduced at the ipso-position to complete the ortho
acylation. Meanwhile, palladium(0) would be regenerated.
To examine this hypothesis, benzoyl chloride and anhydride
were employed as the initial acyl source, and isopropyl
alcohol was used as the hydride source because of our
previous success with this reductant.[19a] Not surprisingly, this
combination in the presence of a base led to severe
esterification without producing any desired ortho-acylation
product.[20] A survey of other common hydride sources, such
as formate salts,[17e] alkyl boronic acids,[21] and tributyltin
hydride, was unfruitful. Thus, in contrast to the previous
reductive ortho-amination reaction,[19a] the compatibility
between the acyl electrophile and the reductant became
a new challenge. The key was to produce the hydride for
palladium in the absence of alcohol nucleophiles.
To address the aforementioned challenge, a unique iso-
propyl carbonate anhydride (2a; see Table 1), available in one
step from the corresponding carboxylic acid,[22] was sought as
a bifunctional reagent. The expected benefits are twofold: 1)
the isopropoxide was masked in the form of a carbonate, thus
minimizing the esterification side reaction; 2) the reagent
contains both the acyl electrophile and hydride source in
a single molecule, thus the operation is simplified. Indeed, by
using 2a as the coupling partner, the desired ortho-acylation
product 4a can be obtained in up to 76% yield when using
[{Pd(allyl)Cl}2] and tri(2-furyl)phosphine as the metal/ligand
combination (Table 1; entry 1). A series of control experi-
ments indicated that the palladium, phosphine ligand,[17b]
NBE, and base were all essential for this transformation
(entries 2–4 and 6). While a simple NBE can promote the
desired transformation (entry 5), use of the amide-substituted
NBE 3 (NBE*; for structure see Scheme 1) was found to give
Table 2: Substrate scope with different aryl iodides.[a]
Table 1: Control experiments for ortho acylation.
Entry
Change from the stanard reaction conditions
Yield [%][a]
1
2
3
none
no [{Pd(allyl)Cl}2]
no P(2-furyl)3
76
0
0
4
no 3
0
5
6
norbornene instead of 3
no Cs2CO3
73
0
7
8
9
10
11
12
no NMe4Cl
60
69
28
12
63
56
Pd(OAc)2 instead of [{Pd(allyl)Cl}2]
PPh3 instead of P(2-furyl)3
K2CO3 instead of Cs2CO3
Pure THF as solvent
608C[b]
[a] All yields are those for isolated products. [b] 708C for 20 h without
CH3CN and NMe4Cl; 1.5 equiv of 2a and 2.0 equiv of Bz2O were used.
[c] 1.0 equiv of NBE* 3 was used. [d] 2.0 equiv of Bz2O and 1.05 equiv of
ClCO2iPr were used instead of 2a and NMe4Cl. [e] 1.5 equiv of 2a and
2.0 equiv of Bz2O were used. MOM=methoxymethyl.
[a] Determined by 1H NMR analysis using 1,3,5-trimethoxybenzene as
the internal standard. [b] Run for 40 h. THF=tetrahydrofuran.
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acetonitrile. Excellent functional-group tolerance was
observed: methyl, benzyl, and trifluoromethyl ethers,
MOM-protected phenols, tertiary amines, THP-protected
alcohols, esters aryl chlorides and bromides, Weinreb
amides, terminal olefins, epoxides, and arylboronic acid
pinacol esters were all tolerated. Furthermore, heteroaryl
iodides such as pyridine, thiophene, and quinoline derivatives
(4q–s), were also suitable substrates, thus implying a good
potential for pharmaceutical applications. For non-ortho-
substituted aryl iodides (e.g 4t), double ortho acylation was
predominant, thus giving 1,3-diacylated arenes. Interestingly,
a tandem cyclization product (4t’) was also isolated in this
case, thus giving a 9-fluorenone derivative.
Scheme 2. Coupling with ipso functionalization.
Next, the scope of anhydrides was explored (Table 3). A
variety of isopropyl carbonate anhydrides were prepared
rapidly in a single step from the corresponding carboxylic
acids and commercially available isopropyl chloroformate.
Both electron-rich and electron-deficient aryl anhydrides
worked under the standard reaction conditions. Enolizable
methyl ketones and ortho thioethers are compatible. Anhy-
drides derived from heteroarenes, such as thiophene, furan,
N-methyl indole, pyrrole, quinoline, and ferrocene, all
successfully coupled in moderate to good yields. Surprisingly,
the alkenyl anhydride preferred to give a cyclized product
(5k), although the reason is unclear. The alkyl carboxylic acid
derivatives also afforded the desired acylation products 5l–n.
To further explore the reaction scope, we found that
functional groups other than hydrogen can also be introduced
at the ipso position, and is analogous to the standard Pd/NBE
catalysis (Scheme 2). Preliminary studies indicated that the
ortho-acylation reaction can be coupled with either a Heck or
Suzuki reaction to install a vinyl or aryl group, respectively, in
a position vicinal to the acyl group.[27] Note that, while the
aryl-B(pin) moiety is intact under the reaction conditions
(Table 2, 4o), aryl boric acids can be effectively coupled.[17a,28]
To gain mechanistic insights of this reaction, a deuterium-
labeling study was performed [Eq. (1)]. When the monodeu-
terated 2a was synthesized and tested under the standard
reaction conditions, more than 95% deuterium was incorpo-
rated at the ipso-position, and thus strongly supports the
proposed hydride-transfer pathway (Figure 1). Notably, the
Table 3: Substrate scope with carbonate anhydrides.[a]
À
monodeuterated product is difficult to access by classical C
H activation.
Finally, the synthetic utility of this method is demon-
strated in the concise synthesis of ketoprofen (sold in
a racemic form),[29] which is a nonsteroidal anti-inflammatory
drug for relieving arthritis-related inflammatory pains or
severe toothaches. Starting with readily available iodoarene
1v,[30] reductive ortho acylation followed by hydrolysis[31]
offered a distinct and efficient strategy to access ketoprofen
(Scheme 3).
In summary, we have developed a reductive ortho-
acylation method for a wide range of aryl iodides using Pd/
NBE catalysis. This transformation introduces an acyl group
and a hydrogen atom at the ortho- and ipso-positions,
respectively, and is enabled by a bifunctional carbonate
anhydride. Broad functional-group tolerance was observed,
and various heterocycles were found to be suitable. We expect
this mode of reactivity could potentially be generalized, thus
allowing other related ortho functionalizations or ortho/ipso
[a] All yields are those for isolated products.
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Acknowledgements
We thank the CPRIT, Frasche Foundation, and Welch
Foundation (F-1781) for funding. G.D. is a Searle Scholar
and Sloan Fellow. Dr. Michael Young is acknowledged for X-
ray crystallography and proofreading the manuscript. We
thank Lin Deng for checking experiments. Johnson Matthey
is thanked for a donation of palladium salts.
À
Keywords: acylation · arenes · C H activation · heterocycles ·
palladium
How to cite: Angew. Chem. Int. Ed. 2015, 54, 12664–12668
Angew. Chem. 2015, 127, 12855–12859
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Received: July 11, 2015
Published online: September 1, 2015
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